An estimated four to five million Americans (about 2% of all ages and 15% of those older than 65) have some form and degree of cognitive impairment. Cognitive impairment or reduction of cognitive functions commonly occurs in association with central nervous system (CNS) disorders or conditions.
Cognition generally refers to the process by which knowledge is acquired, retained and used by subjects. Both memory and thinking are involved in the storage, retrieval, and manipulation of information. Cognitive disorders are abnormalities of thinking and memory that are associated with temporary or permanent brain dysfunction. Their main symptoms include problems with memory, orientation, language, information processing, and the ability to focus and sustain attention on a task. Examples of CNS disorders or conditions that fall within the scope of the present invention include, but are not limited to, age-associated memory impairment (AAMI); mild cognitive impairment (MCI), delirium (aka acute confusional state); dementia (sometimes further classified as Alzheimer's or non-Alzheimer's type dementia); Alzheimer's disease; Parkinson's disease; Huntington's disease (aka chorea); mental retardation; (e.g., Rubenstein-Taybi and Downs Syndrome); cerebrovascular disease (e.g., vascular dementia, post-cardiac surgery); affective disorders; psychotic disorders; autism (aka Kanner's Syndrome); neurotic disorders; attention deficit disorder (ADD); subdural hematoma; normal-pressure hydrocephalus; brain tumor; head trauma (postconcussional disorder) and brain trauma (see DSM-FV, APA 1994). Amnestic and cognitive disorders with or without an established cause are described in DSM-UV. Other cognitive disorders specified in DSM-IV, include learning, motor skills and communication skills disorders (DSM-IV 315.00-315.39). For the purposes of the present invention the terms cognitive impairment and cognitive disorder are deemed to cover the same therapeutic indications. Accordingly, the terms cognitive impairment and cognitive disorder are used interchangeably throughout this application.
Cognitive impairment is typically manifested by one or more cognitive deficits. Memory impairment is a cognitive deficit characterized by the inability to learn new information or to recall previously learned information. Aphasia is a cognitive deficit characterized by a language and/or speech disturbance. Apraxia is a cognitive deficit characterized by the impaired ability to carry out motor activities despite intact motor function according to DSM-UV. Agnosia is a cognitive deficit characterized by the failure to recognize or identify objects despite intact sensory function (as described in DSM-UV). Cognitive impairment may also be manifested by a disturbance in executive functioning (i.e., planning, organizing, sequencing, abstracting). The present invention is directed to a method of treating a subject suffering from a cognitive impairment or a cognitive disorder wherein the cognitive impairment or cognitive disorder is manifested by one or more of the cognitive deficits described herein.
Cognitive impairment or reduction of cognitive function causes significant impairment of social and/or occupational functioning which can interfere with the ability of an individual to perform activities of daily living and greatly impact the autonomy and quality of life of the individual.
Consequently, there is a need for therapies to treat cognitive disorders and cognitive impairments. The indolone compounds of the present invention have now been found to show potent effects in models of cognitive impairment, thereby filling this void in the current state of the art. Applicants further note that the indolone compounds described herein have been previously characterized as GALR3 receptor antagonists (see WO 02/060392), thereby supporting the broader theory that GALR3 receptor antagonists may be useful to treat cognitive disorders.